Community-acquired pneumonia (CAP) and influenza are the 8th most frequent primary and an important secondary cause of death in the US. Information suggests that etiology and possibly frequency of CAP have changed since the last CDC-sponsored population-based study. Even the definition of CAP has undergone revision, with exclusion of a group with the newly-defined healthcare-associated pneumonia (HCAP). Unfortunately, lack of an appropriate population-based pathogen-specific study to define HCAP has now resulted in significant controversy. Conversely, developments in molecular diagnostic techniques, such as urinary antigen testing and polymerase chain reaction (PCR) detection of bacterial and viral genes, have not only made documentation of etiology more accurate than culture-based methods but define etiology in a greater proportion of cases. All these factors coalesce on the need for a contemporary population-based estimate of CAP incidence based on an accurate etiologic diagnosis. In response to this need and the resultant CDC Funding Opportunity, we developed a consortium of three urban Chicago hospitals to recruit 1500 adult CAP patients over an 18 month period. Combining with a previous study at the same centers using a nearly identical protocol will allow accurate estimates over >3years. An accurate population-based estimate of incidence requires inclusion of an urban population with the variety of racial/ethnic, socioeconomic, and access to healthcare characteristics seen in patients admitted to these hospitals. Several subgroups of patients presenting to the hospital with pneumonia are excluded from the current CDC study, such as recent hospital discharges. Since these patients are routinely coded with ICD-9 CAP codes, they will impact our incidence calculations. We will therefore expand inclusion criteria for this proposal to recruit these patients, expecting that molecular diagnostic tools will demonstrate that a high percentage of their pneumonias are caused by usual CAP pathogens. We will also address concern regarding an increased incidence of community-acquired methicillin-resistant S. aureus (CA-MRSA) pneumonia. Microbial etiology will be determined by extensive diagnostic testing, including routine use of urinary antigen detection, paired serology, and a battery of CDC-approved PCR assays. The role of influenza and bacterial co- infection will be aggressively explored with PCR, culture, and paired serology. Whole blood quantitative PCR (qPCR) of a pneumococcal gene and a generic bacterial 16s ribosomal gene will increase diagnostic sensitivity. Confirmation that qPCR correlates with mortality, septic shock, and organ failure will challenge the conventional dogma that these complications are due to the host response rather than bacterial factors. Our data combined with that of other participating centers will provide a more accurate contemporary assessment of pneumonia incidence and etiology. Results will inform future decisions regarding diagnostic testing, empirical antibiotic therapy, and the opportunities for vaccination and other prevention strategies.